ABSTRACT The prevalence of impaired fecundity has been increasing over the last decade and few modifiable risk factors for infertility have been identified. Male factor contributes to 50% of all infertility. In June 2013, with funding from the NICHD (R21-HD072326, R01-HD086742), we launched Pregnancy Study Online (PRESTO) to assess the feasibility of conducting a web-based preconception cohort study in North America and to evaluate determinants of subfertility. Since then, we have recruited more than 4,660 females age 21-45 and 1,206 of their male partners. Virtually all studies of semen quality have been conducted among men seeking fertility treatment in urban centers, thereby limiting generalizability. The enrollment of large numbers of men from the general population prior to conception represents a unique opportunity to assess the feasibility of in-home semen testing. Semen testing that use local labs or specimen mail-in to a central lab involve significant cost. We propose to evaluate the extent to which in-home semen testing is feasible. We will randomize 400 male participants in a 3:1 ratio, with 75% receiving the protocol that involves in-home semen testing + male questionnaire ($20 compensation) and 25% receiving the protocol that involves just completion of the male questionnaire (no compensation). Men in the first arm will be instructed to use TrakTM, a novel FDA-cleared in-home semen testing system. For this study, two tests will be included in each $45 kit allowing for repeated measures of sperm concentration, sperm motility, and semen volume. Subjects will send test results back to investigators via a secure smartphone application. We will assess differences in overall male participation (i.e., questionnaire completion and costs per participant enrolled) across arms and quantify the proportion of men who complete the semen testing protocol. Among the 300 men providing semen data, we will compare the distributions of semen parameters with data from the Stanford infertility clinic and the World Health Organization. Finally, we will evaluate the relation of selected exposures to semen quality, focusing on factors for which studies are scarce or inconclusive such as obesity, physical activity, perceived stress, and clinical depression. We have already shown that appreciable numbers of men are willing to enroll in our preconception cohort study, that men are willing to participate in the proposed protocol for $20, and that the semen data are within the range expected for the general population. The extent to which large scale in-home semen testing will be acceptable to a geographically-heterogeneous cohort of men who are not seeking fertility treatment is unknown. The investigation of men representing the full spectrum of fertility is critical for validly evaluating the role of lifestyle and behavioral factors on fertility. The use of an innovative and cost-effective semen testing method, established infrastructure of PRESTO, prospective collection of risk factor data, and ability to link to semen data to fertility in future analyses are added strengths. If the proposed in-home semen testing methods are shown to be feasible, the inclusion of such methods in future epidemiologic investigations could be paradigm-shifting for the study of male reproductive health.